DESCRIPTION (the applicant's description verbatim): Contrast-enhanced ultrasound has become a valuable experimental and clinical tool for assessing organ perfusion. It used gas-filled microbubbles as perfusion tracers, which scatter ultrasound during their transit through any vascular compartment. Because microbubbles have an intravascular rheology similar to that of red blood cells, contrast-enhanced ultrasound can be used to measure microbubble (or red blood cell) velocity in tissue. Additionally, because the microbubbles remain entirely within the intravascular space, contrast-enhanced ultrasound can also be used to measure the blood volume fraction (MBV). Over this previous grant cycle, we have used MCE to unravel many important aspects of MBV, which have major relevance in understanding the local control of myocardial blood flow (MBF) as well as the adaptive changes that occur consequent to coronary artery disease. In particular, we have gained insights into the role capillaries in regulating MBF. We have shown that capillaries are responsible for limiting the maximal hyperemic response seen in the normal coronary circulation and that capillary blood volume decreases distal to a stenosis during hyperemia. We have also shown that perfusion defects on nuclear tracer imaging is related to reversible decreases in MBV distal to a stenosis rather than due to 'flow mismatch' as has heretofore been assumed. The aim of this proposal is to further define adaptive changes in MBV and capillary resistance that occur under physiological conditions and in atherosclerotic heart disease. The specific aims of this proposal are to assess: 1. How capillaries regulate MBF in the normal coronary circulation when autoregulation is exhausted. 2. What happens to capillaries distal to a stenosis during hyperemia. 3. Whether phasic changes in MBV can be used to detect the presence and magnitude of coronary stenosis at rest. 4. Whether changes in blood viscosity affect coronary blood flow reserve. Studies will be performed in open chest canine models using contrast-enhanced ultrasound and in the rat skeletal muscle using intravital micrscopy. The ultimate aim is the further understanding of the role of capillaries in the local regulation of MBF.